molecular imaging of bone metastasissecure site · osteolytic metastases •waning & guise....

Seite 1

Molecular Imaging of Bone Metastasis

Hojjat Ahmadzadehfar

Seite 2

68%

40%

35%

73%

42%

36%

5%

0

10

20

30

40

50

60

70

80

prostate bladder renal breast thyroid lung GI

Bone metastases Different tumors

urological carcinomas non-urological carcinomas

%

Coleman RE. Clin Cancer Res 2006;12: 6423s-9s; Coleman RE. Cancer Treat Rev 2001;27;165-76; Scher HI et al. Clin Cancer Res 2005;11:5223-32

Skeletal-related events (SRE)

Seite 3

» Pathologic fractures

» Spinal cord compression

» Radiation for bone pain or to treat or prevent pathologic fractures or spinal cord compression

» Surgery

» Bone pain

» Hypercalcemia of malignancy

Quality of Life

Molecular Mechanisms of Bone Metastasis

•Guise T et al. BasicMechanisms Responsible for Osteolytic and Osteoblastic BoneMetastases. Clin Cancer Res 2006;12:6213S-16S

•Waning & Guise. Molecular Mechanisms of Bone Metastasis and Associated Muscle Weakness. Clin Cancer Res 2014; 20(12); 3071–7

•Chiang & Messague. Molecular Basis of Metastasis. N Engl J Med 2008;359:2814-23

•Yin et al. Mechanisms of cancer metastasis to the bone. Cell Research, 15(1):57-62, Jan 2005

• bone metastases are the result of complex interactions among tumor

cells, bone cells, and the bone microenvironment.

1- tumor cells must detach from the primary tumor

2- enter the systemic circulation (intravasation)

3- evade detection by the immune system

4- adhere to capillaries in the bone marrow leading to extravasation into the

bone marrow space

Seite 4

Molecular Mechanisms of Bone Metastasis Osteolytic metastases



• Osteolytic metastasis is the most common form of bone metastasis in all cancer

patients.

• Osteolytic metastases are associated with increased osteoclast activity and

reduced osteoblast activity that is uncoupled from bone resorption

Seite 5

• CXCR4: promotes osteolytic bone metastasis • PTHrP: is one of the major mediators of Breast cancer related osteolytic bone metastasis • IL-6 is constitutively expressed by renal, bladder, prostate, cervical, glioblastoma and breast carcinoma cells. It is a potent stimulator of osteoclast formation and can enhance the effects of PTHrP on osteoclasts • IL-1, TNF and prostaglandins which increase RANKL expression and stimulate osteoclasts

Molecular Mechanisms of Bone Metastasis Osteoblastic metastases



• Endothelin-1 (ET-1): ET-1 drives net bone formation by inhibiting osteoclast

bone resorption and osteoclast motility

• BMPs (bone morphogenic protein ): stimulate osteoblast differentiation through

the activation of transcription factors, in particular Runx-2

– In patients with prostate cancer BMP expression has been shown to

correlate with increased recurrence rates and decreased survival

• uPA (urokinase-type plasminogen receptor): uPA can cleave and activate

TGFβ; TGFβ regulates osteoblast and osteoclast differentiation but also

regulates the growth of tumor cells themselves

• PSA: PSA can cleave PTHrP and therefore could block bone resorption

• Platelet-derived growth factor (PDGF)

Seite 6

Seite 7

Seite 8

Imaging agents

Imaging of bone turn over

99mTc-MDP, HDP 18F-Fluorid 68Ga-Bisphosphonate

Imaging of metabolic/tumoral

changes

18F-FDG 18F-FLT 123/131I-MIBG 131I 68Ga-DOTATOC 68Ga/18F-PSMA 18F-Choline

Bone Scintigraphy 99mTc-labeled diphosphonates

Azad et al.: Molecular and Functional Imaging of Bone Metastases in Breast and Prostate Cancers. (Clin Nucl Med 2016;41: e44 – e50

• It has been the most widely performed investigation for diagnosing

metastatic bone disease and monitoring treatment response.

• Uptake of these radiotracers depends on local blood flow and

osteoblastic activity but does not reflect the true tumor burden in the

bone marrow.

• Peak bone uptake occures approximately 1 hour after injection

• Highest target to background ratio is 6-12 hours after injection

• Images are typically taken 2-4 hours

Seite 9

The Requisites. Nuclear Medicine 4th edition. H. Ziesmann et al.

Bone Scintigraphy SPECT/CT against low specificity

Seite 10

Complementary use of SPECT-CT can significantly improve the specificity of

bone scintigraphy.

SPECT-CT has a significant impact on clinical patient management by

reducing the rate of unclear findings and allowing a more accurate

assessment of the osseous tumour load

A definite diagnosis can be achieved in more than 95% of the patients


Seite 11

patient with breast cancer

Osteochondrosis in C6/C7 Römer et al. SPECT-Guided CT for evaluation foci of increased bone metabolism classified as indeterminate on SPECT in cancer patients. J Nucl Med.

2006 Jul;47(7):1102-6


Seite 12 Osteolysis in C 5

patient with breast cancer

Römer et al. SPECT-Guided CT for evaluation foci of increased bone metabolism classified as indeterminate on SPECT in cancer patients. J Nucl Med.

2006 Jul;47(7):1102-6

Seite 13


More than 90% of cancer patients leave the clinic with a definite diagnosis

Malignant

Indeterminate

Benign

44

52

28

0

25

50

75

100

125

SPECT

Lesions

43

77

SPECT•CT

4

SPECT vs. SPECT•CT

Diagnostic in Oncology

Römer et al. SPECT-Guided CT for evaluation foci of increased bone metabolism classified as indeterminate on SPECT in cancer patients. J Nucl Med.

2006 Jul;47(7):1102-6

Seite 14 Palmedo et al. EJNMMI


p = 0,01

All patients (406)

Palmedo et al. EJNMMI

Bone Scintigraphy 99mTc-labeled diphosphonates

Azad et al.: Molecular and Functional Imaging of Bone Metastases in Breast and Prostate Cancers. (Clin Nucl Med 2016;41: e44 – e50

•There is often a delay before treatment response becomes apparent on

BS due to ongoing reparative osteoblastic activity, which may cause the

flare phenomenon.

•The determination of response with BS may take 4 to 6 months, meaning

that patients may stay on potentially ineffective and toxic treatments for

longer than necessary.

Seite 15

Bone Scintigraphy vs metabolic imaging PSMA

Seite 16

• Prostate-specific membrane antigen (PSMA) is

highly expressed on prostate epithelial cells and

strongly up-regulated in prostate cancer

• The PSMA expression levels are directly

correlated to androgen independence, metastasis,

and PCa progression

10/2015 03/2015

PSMA-PET PSMA-PET Bone scintigraphy Bone scintigraphy

Bone Scintigraphy vs metabolic imaging PSMA

Bone Scintigraphy No detection of bone marrow metastases

The Requisites. Nuclear Medicine 4th edition. H. Ziesmann et al.

• In patients with PSA levels < 10 ng/ml , bone metastases are rarely

found (< 1% of the times)

• Scintigraphy is still indicated to evaluate symptomatic patients and

suspicious areas seen radiographically.

• With increasing PSA levels, the chance of detection metastatic disease

increases

Seite 18

72 y FD: 2010, Gleason: 8, Hx of enzalutamide and abiraterone, Hx of CTx

PSA:627 LDH:230 ALP:61

Bone Scintigraphy vs tumor imaging using PSMA

Bone targetet Therapy using Ra-223

PSMA-PET as gate-keeper

Seite 20

68Ga-PSMA-11 99mTc-MDP

Ahmadzadehfar H. et al. 68Ga-PSMA-11 PET as a Gatekeeper for the Treatment of Metastatic Prostate Cancer with 223Ra: Proof of Concept

Ahmadzadehfar H. et al. 68Ga-PSMA-11 PET as a Gatekeeper for the Treatment of Metastatic Prostate Cancer with 223Ra: Proof of Concept. JNM2017

Only with bone scan

Bone scan + PSMA-PET

63 patients: 307 cycles; at least 2 cycles

PSA-decline: 12.9% PSA-decline > 50 %: 3.2 %

PSA-decline: 43.8 % PSA-decline > 50 %: 25 %

p=0.007

Seite 21

Bone targetet Therapy using Ra-223

PSMA-PET as gate-keeper

Bone PET 18F-Fluorid

Cook.: 18 F-Fluoride PET and PET/CT Imaging of Skeletal Metastases. PET Clin 5 (2010) 247–257 Seite 22

A rectilinear 18 F-fluoride bone scan of a patientwith metastatic breast cancer

performed in 1973 in Guys Hospital, London.


Apostolova & Brenner.: Measuring bone metabolism with fluoride PET: methodological considerations. PET Clin 5 (2010) 247–257

• 18F-Fluoride ion is extracted by the skeletal system in proportion to bone

blood flow and osteoblastic activity.

• The upper limit of the total amount of isotope that can be deposited in

bone in a given time is imposed by perfusion of the bone (perfusion-

limited uptake).

• As soon as the specific activity in the blood has fallen below that on the

bone surface, the concentration on the bone begins to decrease owing

to reverse exchange.

• The concentration of 18F-fluoride in bone was found to reach a

maximum 2 to 3 hours after injection and then began to decrease

slowly. One hour after administration of 18F-fluoride, only about 10% of

the injected activity remains in the blood.

Seite 23


Seite 24

18F-Fluoride bind only minimally to plasma proteins

Acquisition time: 1 h p.i.

Higher sensitivity

Whole body 3D imaging Sensitivity of PET/CT:99% Specificity of PET/CT: 97 %

SUV measurement

99mTc-MDP Approximately 30% of Tc-bisphosphonates are

protein bound immediately after injection; this fraction increases approximately 70% by 24 h

after injection

Acquisition time: 2-4 h p.i.

Lower FP

3D imaging partly possible Sensitivity:86%

Specificity: 78 % (91% SPECT/CT)

Quantification is not easily possible

Seite 25

Bone Scan

Semiqantification

EXINI software

Fosbol et al.

Radium‐223 therapy of advanced metastatic castration‐resistant prostate cancer: quantitativeassessment of skeletal tumor burden for prognostication of clinic

al outcome and hematological toxicity. JNM 2017

Seite 26

Bone Scan

Semiqantification

Fosbol et al.

Radium‐223 therapy of advanced metastatic castration‐resistant prostate cancer: quantitativeassessment of skeletal tumor burden for prognostication of clinic

al outcome and hematological toxicity. JNM 2017

Univariate and multivariate Cox proportional hazard regression model of predictors of OS

18F-Fluorid

Prognostic utility

Brito et al. 18 F-Fluoride PET/CT tumor burden quantification predicts survival in breast cancer. Oncotarget, 2017, Vol. 8, (No. 22), pp: 36001-36011

• 18F-Fluoride PET/CT tumor burden quantification predicts survival in

breast cancer

• 107 breast cancer patients

TLF10: the total activity of F-Fluoride-avid metastases (skeletal tumor

burden)

Rohre et al. Determination of Skeletal Tumor Burden on 18 F-Fluoride PET/CTJ Nucl Med. 2015 October ; 56(10): 1507–1512

18F-Fluorid

Prognostic utility in breast cancer

Brito et al. 18 F-Fluoride PET/CT tumor burden quantification predicts survival in breast cancer. Oncotarget, 2017, Vol. 8, (No. 22), pp: 36001-36011

• 18F-Fluoride PET/CT tumor burden quantification predicts survival in

breast cancer

• 107 breast cancer patients

TLF10: the total activity of F-Fluoride-avid metastases (skeletal tumor

burden)

Seite 28

TLF10= 641 TLF10= 1039 TLF10= 39409

18F-Fluorid


Brito et al. 18 F-Fluoride PET/CT tumor burden quantification predicts survival in breast cancer. Oncotarget, 2017, Vol. 8, (No. 22), pp: 36001-36011 Seite 29

PFS

18F-Fluorid


Brito et al. 18 F-Fluoride PET/CT tumor burden quantification predicts survival in breast cancer. Oncotarget, 2017, Vol. 8, (No. 22), pp: 36001-36011 Seite 30

PFS

25.8 months

4.13 months

P<0.0001 Significant predictor of OS and bone events

18F-Fluorid

Prognostic utility in prostate cancer

Etchebehere et al. Prognostic Factors in Patients Treated with 223 Ra: The Role of Skeletal Tumor Burden on Baseline 18 F-Fluoride PET/CT

in Predicting Overall Survival. J Nucl Med 2015; 56:1177–1184 Seite 31

42 patients with CRPC underwent 223Ra and a baseline fluoride PET/CT scan.

18F-FDG PET

Jeong et al. Incidental uptake in the breast on FDG PET/CT: Multimodality imaging features and pathologic correlation. ECR 2014 /C1295 Seite 32

FDG is taken up by the tumor itself, but ……

18F-FDG PET

Seite 33

FDG uptake depends on ……

-Tumor entity

-Tumor histopathology - e.g. in breast cancer higher FDG uptake in ER negative, ductal carcinoma

-Time of the scan - treatment-naïve vs Hx of therapy

Gil-Rendo A et al. Association between FDG uptake and prognostic parameters in breast cancer. Br J Surg 2009;96(2):166e70.

High detection rate in osteolytic metastasis Lower sensitivity in osteoblastic metastasis????

Israel O. et al. FDG-PET and CT patterns of bone metastases and their relationship to previously administered anti-cancer therapy. EJNMMI 2006

• Most untreated bone metastases are PET positive and lytic on CT, while

in previously treated patients most lesions are PET negative and blastic

on CT.

A 40-year old woman

with breast cancer

6 months following CTx

18F-FDG PET Time of the imaging

FDG PET/Fluorid PET Coctail

Bone metastases

Roop et al. Incremental Value of Cocktail F-FDG and F-NaF PET/CT Over F-FDG PET/CT Alone for Characterization of Skeletal Metastases in Breast

Cancer. Clin Nucl Med 2017;42: 335 – 340

• 70 patients with BC or recurrent breast cancer were prospectively recruited in the study.

• FDG PET + FDG/Fluorid PET

Exclusion criteria:

uncontrolled diabetes, surgery in the last 4 weeks, chemotherapy in the last 2 weeks, radio-

therapy in the last 6 weeks, current pregnancy, or lactation

Neuroendocrine Neoplasia PET tracers

18F-FDG

18F-DOPA

18F-FDA ([18F]F|uorodopamine)

68Ga-DOTATOC & 68Ga-DOTATATE (sst2 receptor specific)

68Ga-DOTANOC (sst2,3,5 receptor specific)

SSRT imaging

PET vs scintigraphy

68Ga-DOTATOC PET/CT

limited availability

Investigation time: < 2 h

Radiation exposure: 3 mSv

111In-Octreotide

Investigation time > 24 h

Radiation exposure: 9 mSv

Sensitivity 90% Sensitivity 70%

SSTR imaging vs bone scan Tumor specific imaging

Sabet, ……., Ahmadzadehfar H. Nuklearmedizin. 2012;51(3):95-100

177Lu-DOTATATE 99mTc-MDP

Comparison between bone scintigraphy and 177Lu-DOTATATE-Imaging

• 29 patients with GEP-NET • Bone scintigraphies was done within four weeks

of initiation of PRRT • Gold-Standard: MRI/CT and PET/CT imaging

• In 65 % of cases Lu-DOTATATE-scan was superior • In 35 % both modalities were comparable

123I-MIBG Tumor specific imaging

» 4 y/o with a Hx of stage 4 NB, since two years in remission after treatment

Seite 40

Theranostics

Why do we need so many radiopharmaceutical for the imaging of

bone and bone marrow metastases?

Whole body MRI Whole body CT

Yordanova et al. Theranostics in nuclear medicine practice. Oncotarget and therapy 2017

Neuroblastoma MIBG vs SSTR imaging

12/2015 12/2015 02/2016

68Ga-DOTATOC PET 123I-MIBG 24h p.i.

Lu-DOTATATE Tx

Malignant pheochromocytoma MIBG vs SSTR imaging

68Ga-DOTATOC PET 123I-MIBG 24h p.i.

Summary

• Bone imaging vs bone marrow imaging

• Tumor type and histopathology

• Time of imaging and stage of the disease

• Theranostics approach

• We need more specific tracers

Hojjat Ahmadzadehfar, MD, MSc

Associate Professor

Head of the therapy section

Department of Nuclear Medicine

University Hospital Bonn

molecular imaging of bone metastasissecure site · osteolytic metastases •waning & guise....

Documents